Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.69 (APC)
 16,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Conversion by alpha-thrombin of the zymogen human protein C (HPC) to activated protein C (aPC) is an important physiologic feedback control mechanism for the coagulation cascade. Although activation of HPC by thrombomodulin-bound thrombin is relatively rapid, activation by free thrombin occurs at a significantly slower rate. Previously, we generated a "hyper-activatable" derivative of HPC (FLIN-Q3) with an increased activation rate by free alpha-thrombin in vitro. In this study, the antithrombotic efficacy of FLIN-Q3 was compared with both native zymogen and aPC in an arteriovenous shunt model of thrombosis in the guinea pig. Recombinant proteins were infused 15 minutes before and throughout a 15-minute period while blood was circulated from carotid to jugular through tubing that enclosed a thread on which fibrin was deposited. Parallel dose-dependent antithrombotic responses were observed. Under these non-steady-state conditions, the calculated infusion doses associated with a 50% reduction of thrombus mass were 2.7, 24, and 250 mg/kg/h for aPC, FLIN-Q3, and HPC, respectively. Thrombus weight correlated inversely with plasma concentration of aPC, measured amidolytically, from either direct infusion of aPC or that generated from the zymogens in the animal, and similarly correlated inversely with anticoagulant activity measured by whole blood aPTT. Neither zymogen form showed significant aPC activity before shunt circulation, suggesting a requirement for exposure to thrombin. After the infusion was discontinued for 15 minutes, a second period of thrombus formation in the shunt demonstrated the ability of zymogen forms of PC, unlike aPC, to provide "on-demand" anticoagulant responses to repeated thrombotic stimuli. Thus, a "hyper-activatable" PC molecule such as FLIN-Q3 may represent a superior form of anticoagulant therapy than either the native zymogen or aPC.
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PMID:Antithrombotic efficacy in the guinea pig of a derivative of human protein C with enhanced activation by thrombin. 900 56

Vipera lebetina fibrinogenase (VlF) was shown to render fibrinogen incoagulable and to solubilize fibrin. The fibrinogenolytic activity of this enzyme was found to be 33 mg fibrinogen/min/mg protein. The study of the specificity of this enzyme revealed that it has no effect on purified factor X, prothrombin and protein C and on the specific chromogenic substrates of their active form. Plasminogen was not activated by VlF but slightly degraded. We have also compared the effect of VlF and plasmin on fibrinogen and shown that these two enzymes have a different sites of cleavage. This enzyme inhibited human platelet aggregation on PRP initiated by ADP and collagen but was without effect on the aggregation of washed rabbit platelets using thrombin as agonist. Administration of VlF in rat did not show any necrosis or hemorrhage in treated rats organ's. We therefore, examined the thrombolytic activity of VlF in a rat model of venous thrombosis. Thrombus was produced in the posterior vena cava by injection of human fibrinogen and thrombin. Injection of 5 mg/Kg body weight showed an evident flow restoration after one hour and measurement of the fibrinogen level a decrease of about 30% after 3 hrs. VlF's action is not dependent on plasminogen activators and may act synergistically with them, thereby providing an intriguing potential clinical application for dissolution of blood clots.
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PMID:Further characterization and thrombolytic activity in a rat model of a fibrinogenase from Vipera lebetina venom. 917 44

Resistance to activated protein C is a recently detected phenomenon that has gained a rapid acceptance as a major risk factor for venous thromboembolism. The phenotypic expression of resistance to activated protein C is characterized by a poor response to the anticoagulant activity of activated protein C, a key enzyme in the down-regulation of blood coagulation, which causes a disposition for a hypercoagulable state. At least 90% of the cases with resistance to activated protein C are explained by a point mutation in the gene for coagulation factor V, resulting in replacement of an Arg to Gln at position 506 (factor V:Q506, often denoted factor V Leiden), one of the three activated protein C cleavage sites in activated factor V. The mutation is inherited as an autosomally dominant trait and has a prevalence of 2% to more than 10% in the general Caucasian population. A number of clinical studies, using different inclusion criteria, show a prevalence of activated protein C resistance of 20-60% among patients with venous thromboembolism. The actual thrombotic risk is moderate with an odds ratio of 5-7 but its high prevalence makes it by far the most important inherited risk factor known today, even higher than the sum of contributions from inherited deficiencies of antithrombin, protein C and protein S. Recent data suggest that activated protein C resistance, which is not due to factor V:Q506 and which appears to be acquired, is also a risk factor for venous thrombosis and for cerebral ischaemic disease. A decreased response to activated protein C is common during pregnancy and during use of oral contraceptives, but the clinical relevance of these findings have yet to be determined. The activated protein C resistance phenotype is typically diagnosed with an activated partial thromboplastin time-based assay, which detects factor V:Q506-dependent as well as acquired activated protein C resistance. However, the sensitivity and specificity for the factor V mutation are usually below 90%. Coagulation instruments with a turbidimetric or photometric clot detection principle generally provide a better performance as compared to electromechanical instruments. The activated partial thromboplastin time test requires careful control of preanalytical variables and platelet contamination should be below 1% since otherwise a falsely low activated protein C response will be obtained. A sensitivity and specificity of close to 100% for factor V:Q506 is obtained in a modified activated partial thromboplastin time test using predilution of sample plasma with factor V deficient plasma. The influence of preanalytical variables in this assay is minor. A number of polymerase chain reaction-based methods, some of them allele-specific, have been published, which provide convenient and objective confirmation of the factor V mutation. Thrombotic events are often triggered through the presence of a combination of inherited and circumstantial risk factors. The high prevalence of activated protein C resistance raises the issue whether it would be cost-beneficial to screen for this trait in connection with surgery, pregnancy and oral contraceptives. Some data already support this, but prospective studies will be necessary to delineate under which circumstances this might be implicated.
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PMID:Activated protein C resistance--a major risk factor for thrombosis. 926 26

The purpose of this study was to examine the relationship among adverse pregnancy outcome, the presence of thrombotic lesions in the placenta, and the frequency and type of laboratory abnormalities consistent with the presence of a thrombophilic state. A retrospective cohort study was designed to determine the frequency of laboratory abnormalities consistent with thrombophilia among patients with thrombotic lesions of the placenta and adverse pregnancy outcome. The workup for a thrombophilic state included anticardiolipin antibodies, lupus anticoagulant, protein C and antithrombin III activities, protein S total and free, activated protein C resistance ratio, and Factor V Leiden mutation. Thrombotic lesions were identified by histopathologic examination of the placenta. Thirteen patients met the study criteria over an 11-month period. Seven patients were heterozygous for Factor V Leiden mutation (53.8%). Protein S deficiency was found in three cases (23.0%), and no hemostatic abnormality was detected in three cases (23.0%). Mothers with an adverse pregnancy outcome and thrombotic lesions of the placenta often have laboratory abnormalities indicative of a thrombophilic state. We propose that thrombophilia leading to thrombosis in the maternal and/or fetal circulations is a significant mechanism of disease during pregnancy.
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PMID:Thrombophilia: a mechanism of disease in women with adverse pregnancy outcome and thrombotic lesions in the placenta. 984 93

This report characterizes risk factors in patients who suffer pulmonary embolus (PE) after insertion of vena caval filter (VCF) and formulates an organized diagnostic and therapeutic plan of management. Three hundred eighteen patients were included in a review of patients undergoing insertion of VCF from 1989 to 1995. Ten patients (six men and four women, ages 25-72 years) from this group (3.1%) experienced PE after VCF insertion. Risk factors for deep venous thrombosis were documented in these ten patients. Venacavography was performed after diagnosis of PE. Thrombus length measured from the apex of the filter was used to determine further therapy. Thrombus 5 cm or greater in length was treated with a second VCF (VCF-2). Smaller clots were treated with anticoagulation (AC). All patients treated with AC underwent repeat vena caval study (CT scan or venacavagram) 10 days to 18 months after treatment. PE occurred from 8 days to 5.5 years after original VCF insertion. Five patients suffered PE longer than 6 months (range, 21-66 months; mean, 39 months) after VCF insertion. Venacavagrams demonstrated thrombus in all ten patients with PE. Six patients were treated with VCF-2 and four patients with AC. Dissolution of thrombus was seen on follow-up in all patients given AC. All 10 patients harbored at least two risk factors for deep venous thrombosis. Malignancy was found in only two patients. Five patients were found to have procoagulant states characterized by decreased levels of anti-thrombin III or protein C or S. No postoperative deaths or early recurrent PE occurred. One patient experienced another PE 5 years after treatment with AC when she discontinued warfarin. Contraindications to AC appeared to be self-limited, and all patients were discharged on warfarin. No significant bleeding occurred during early follow-up. Our findings confirm the reliability and low complication rate for VCF. Patients experiencing PE after insertion of VCF mandate an aggressive diagnostic approach that should include venacavography and a search for identifiable risk factors including procoagulant state. Treatment with AC and insertion of a second VCF both give favorable results. All patients appear to benefit from short- or long-term warfarin therapy, and contraindications to AC frequently are self-limited. Therapy based on clot size warrants further study.
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PMID:Pulmonary embolus after vena cava filter placement. 1019 Mar 60

Thrombotic lesions are consistently observed in chronic thromboembolic pulmonary hypertension (CTEPH) and frequently found in primary pulmonary hypertension (PPH). It remains unknown, however, whether thrombosis is related to defects of the antithrombotic pathway or to previous vascular injury. This study therefore analysed the frequency of both hereditary and acquired thrombotic risk factors in CTEPH and PPH. One hundred and forty-seven consecutive patients with CTEPH investigated in the author's institution were compared to 99 consecutive patients with PPH. In 116 CTEPH patients and 83 PPH patients, phospholipid-dependent antibodies (antiphospholipid antibodies and lupus anticoagulant) were analysed by both immunological and clotting assays. In patients enrolled since 1994 (46 CTEPH and 64 PPH), hereditary thrombotic risk factors were also determined. Antithrombin, protein C and protein S activities were measured by functional assays. Mutations of factor V and factor II were identified by polymerase chain reaction. The prevalence of hereditary thrombotic risk factors was not increased in patients with either PPH or CTEPH. In contrast, a high frequency of phospholipid-dependent antibodies was observed in PPH (10%) and more notably in CTEPH (20%). Moreover, in PPH, antibodies were present only in low titre whereas in CTEPH, half of the patients with antiphospholipid antibodies had high titres. In addition, in CTEPH all but one of the patients with lupus anticoagulant also had antiphospholipid antibodies. The most striking finding of this study was the high prevalence of phospholipid-dependent antibodies but their clinical relevance appears to be different in primary pulmonary hypertension and chronic thromboembolic pulmonary hypertension. In primary pulmonary hypertension, these antibodies in low titre probably reflect endothelial dysfunction. In contrast, in chronic thromboembolic pulmonary hypertension the presence of antibodies in high titre associated with lupus anticoagulant, underlines the role of thrombosis in the pathogenesis of this condition.
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PMID:Thrombotic risk factors in pulmonary hypertension. 1093 6

In high-risk and complicated coronary intervention, the risk of acute closure is unpredictable. Thrombus and platelet deposition at the intervention site may also have further effects on subsequent restenosis. In vivo infusion of activated protein C has previously been shown to achieve potent anticoagulation without any haemostatic side effects. We now evaluated the in vitro and in vivo efficacy of polymer-coated coronary stents loaded with purified rabbit Activated Protein C (APC). By measuring 125I-fibrinogen/fibrin deposition APC-loaded stent-wires were antithrombotic compared to albumin-loaded, inhibited-APC-loaded, plain polymer-coated and stainless steel stent-wires. In a balloon injury rabbit iliac artery model, APC-loaded stents did not occlude (0/14) compared to plain stents (9/15) and BSA-loaded stents (2/4). Relative 111In-labelled platelet deposition showed a similarly significant degree of inhibition. In conclusion, APC-loading could render stents significantly less thrombotic. Whether an effective antithrombogenic stent like this effectively reduces restenosis rates warrants further evaluation.
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PMID:Inhibition of platelet thrombosis using an activated protein C-loaded stent: in vitro and in vivo results. 1074 60

Recently, basic and clinical advances have provided insights into the molecular events that link inflammation with blood coagulation and thrombosis. At least in cell culture, the inflammatory cytokines, especially tumour necrosis factor alpha (TNF) and interleukin 1-beta (IL-1), are major mediators that can elicit changes in cell phenotype. With respect to coagulation, one of the clot-promoting and one of the inhibitory pathways seem especially prone to modulation by these cytokines. Whenever Tissue Factor contacts the blood, coagulation is initiated rapidly. These cytokines can elicit Tissue Factor production on endothelium and monocytes. Thus, the cytokines elaborate Tissue Factor formation intravascularly. This contrasts with the normal situation in which Tissue Factor is located exclusively in the extravascular space, largely on fibroblasts, where it is expressed constitutively. Furthermore, cytokines, especially interleukin 6 (IL-6), can stimulate new platelet formation, and the new platelets responding to IL-6 have increased sensitivity to thrombin activation and increased procoagulant activity. Regulating the clotting process are a large number of anticoagulant and fibrinolytic mechanisms. The three major anticoagulant mechanisms appear to involve antithrombin-heparin, Tissue Factor pathway inhibitor (TFPI) and the Protein C pathway. Of these, the Protein C pathway appears to be the primary target for cytokine action. The Protein C pathway is initiated when thrombin binds to thrombomodulin (TM). TM is expressed constitutively on endothelium. In tissue culture, TNF, IL-1 or endotoxin lead to a slow loss of TM and endothelial cell Protein C receptor (EPCR) from the cell surface. In addition, Protein S levels decrease in patients with disseminated intravascular coagulation (DIC). Taken together, these results suggest that cytokines should elicit massive thrombotic responses when administered systemically. At near toxic levels, TNF fails to elicit an overt DIC or thrombotic response in patients, although sensitive markers of coagulation do detect changes in coagulation in response to TNF. In baboons, very high levels of TNF also fail to elicit fibrinogen or platelet consumption. However, if the Protein C pathway is blocked, these cytokines can elicit either DIC or deep-vein thrombosis, depending on the conditions. Thrombus formation is potently potentiated by impeding flow and/or by catheterization. DIC is facilitated by providing membrane surfaces, possibly mimicking complement mediated platelet activation/damage that occurs in shock. Thus, available evidence suggests important roles for inflammatory cytokines in DIC and thrombosis, but they seem insufficient by themselves to elicit overt thrombotic responses without secondary stimuli. Current data suggest that anti-inflammatory drugs are a viable candidate to blocking DIC or thrombosis without impairing the haemostatic balance.
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PMID:Possible involvement of cytokines in diffuse intravascular coagulation and thrombosis. 1085 74

Thromboembolic disease (TED) has been recognized as a complication of inflammatory bowel disease (IBD) since the 1930s (Bargen & Barker 1936). The relative contributions of inherited or acquired thrombophilia and the inflammatory response to the mechanism of this tendency is unclear. Thrombotic events are more common in active disease although significant numbers also occur spontaneously, when the disease is in clinical remission (Talbot et al. 1986; Jackson et al. 1997). Studies looking at the prevalence of specific thrombophilic states such as Antithrombin III deficiency (Jackson et al. 1997; Lake, Stauffer & Stuart 1978; Cianco et al. 1996; Ghosh et al. 1983), Factor V Leiden mutation (APC Resistance) (Jackson et al. 1997; Probert et al. 1997; Ardizzone et al. 1998; Liebman et al. 1998), anticardiolipin antibodies (Ciancio et al. 1996), Protein C (Wyshock, Caldwell & Crowley 1988; Korsten & Reis 1992) and Protein S deficiencies (Jorens et al. 1990; Aadland et al. 1992) in IBD have been contradictory or equivocal. We had previously found that IBD patients with a history of TED are not more likely to have a laboratory thrombophilic abnormality than those with uncomplicated disease. We also demonstrated that the prevalence of heterogenous laboratory thrombophilic abnormalities (usually minor) in all IBD patients may be as high as 60%, much higher than the recognized prevalence of TED (Lim, Jones & Gould 1996). We wondered how this would compare with the healthy non-IBD population. We have therefore explored the prevalence of such thrombophilic abnormalities in a group of IBD patients who had no history of TED and compared them with healthy age and sex matched controls.
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PMID:Laboratory findings associated with thrombophilia are not more common in inflammatory bowel disease. 1101 40

Thrombotic disease is less frequent in children than in adults, but may result in severe morbidity and mortality. The coagulation system is balanced to provide rapid activation to stop bleeding and appropriate inhibition to prevent unwanted clot extension. It is regulated by fibrinolysis and by three major anticoagulant pathways: the protein C, antithrombin, and tissue factor pathway inhibitor systems. Acquired or inherited abnormalities of coagulation proteins or hemostatic regulatory mechanisms, particularly when combined with dehydration or the presence of indwelling catheters, may pose a high risk for thrombosis. Thrombosis in a child warrants investigation of potential underlying prothrombotic conditions. These include acquired antiphospholipid antibodies or the lupus anticoagulant as well as abnormalities of the inherited anticoagulant factors including protein C, protein S, antithrombin, and Factor V Leiden. Other abnormalities may result in heightened levels of otherwise normal coagulation proteins such as hyperprothrombinemia due to the prothrombin 20210 mutation. A large survey of children with thrombosis indicated that Factor V Leiden, protein C deficiency, and increased lipoprotein(a) were found most commonly. The most severe predisposition occurs with homozygous protein S or protein C deficiency with resultant purpura fulminans in the newborn. The risk of thrombosis in children with heterozygous deficiencies of anticoagulant proteins is not well defined, although it is clear that combined heterozygotes or a combination of an inherited and an acquired defect heightens the risk for thrombosis. Treatment of thrombosis primarily involves a rapidly acting anticoagulant such as heparin or low-molecular-weight heparin to prevent extension, and long-term anticoagulation with warfarin may be instituted to prevent recurrence. Fibrinolytic therapy is infrequently used because of the risk of serious bleeding complications and is reserved for selected cases of arterial thrombosis to initiate rapid reperfusion of ischemic tissue or used in those patients with a large venous thrombosis and pulmonary emboli causing hemodynamic compromise.
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PMID:Anticoagulant proteins in childhood venous and arterial thrombosis: a review. 1111 87


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